The personal, social and criminal ramifications of cocaine abuse and dependence are enormous problems in North America, and yet no proven pharmacotherapies are available. A point in the cycle of addiction where pharmacological intervention can be particularly beneficial is to interfere with the overwhelming motivation by addicts to relapse to drug use. The primary goal of the Neurobiology of Addiction Research Center (NARC) for the last 9 years has been to identify the neuropathology that underpins the drive to engage in cocaine seeking. In this renewal application the NARC has 3 Cores (Administrative, Animal & Pilot), and 4 Scientific Projects. A primary unifying scientific theme of the NARC is that a key neurological consequence of chronic cocaine use is an impairment in 'top-down' control of drug seeking and relapse that resides in pathological changes in the projection from the prefrontal cortex (PFC) to the nucleus accumbens. All projects evaluate this general hypothesis using a variety of approaches, ranging from animal models of relapse, to in vivo and in vitro electrophysiological measurements of pathway function, to morphological changes in neuron structure and biochemical changes in cell signaling. These techniques are combined with state-of-the-art optogenetic and transgenic approaches to validate involvement of the PFC to accumbens projection and dopaminergic afferents to the projection. In addition to circuitry, a key mechanism of NARC synergy is that all projects use rats generated by the animal core, providing consistency in animal models and in the use of optogenetic reagents among the projects. Other important points of synergy within the NARC are through well-established outreach programs to undergraduate and high school students, and through its Pilot Core which involves all faculty in mentoring activity, as well as allows some findings to move into pilot clinical trials. In summary, the renewal of the NARC contains experienced investigators who will bring to bear and integrate new technologies towards understanding how cocaine affects PFC regulation of cocaine seeking, and who will actively mentor new investigators and students towards quality research in the field of addiction neurobiology.